Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction
Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction
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DOI：
10.1016/j.canlet.2011.04.024
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发表时间：
2011-09-28
期刊：
影响因子：
9.7
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Hiwatashi, Kiyokazu;Tamiya, Taiga;Yoshimura, Akihiko
炎症已被证明在肿瘤发生、肿瘤进展和转移中起重要作用。STAT 3已被证明在多种人类癌细胞中频繁激活，并且STAT 3信号传导促进肿瘤细胞的生长和存活。然而，STAT 3在骨髓细胞中的作用与肿瘤相关，目前尚不清楚。细胞因子信号转导抑制因子-3（SOCS 3）已被证明是STAT 3的负调节因子。在这项研究中，我们使用巨噬细胞特异性SOCS 3条件性敲除（cKO）小鼠来研究巨噬细胞中STAT 3的过度活化对肿瘤发展和转移的影响。在B16 F10黑色素瘤细胞的皮下移植模型中，尽管肿瘤大小没有显著差异，但SOCS 3-cKO小鼠的存活时间长于野生型（WT）小鼠。当B16 F10经静脉内激发时，SOCS 3-cKO小鼠表现出比WT小鼠更少的肺和肝转移性肿瘤结节。在体外用肿瘤裂解物刺激的SOCS 3（-/-）巨噬细胞表现出延长的STAT 3磷酸化，并且产生比WT巨噬细胞更少量的TNF α和IL-6以及更大量的MCP 2/CCL 8。MCP/CCL 8通过STAT 3诱导并在WT小鼠中表现出抗肿瘤转移作用。这些数据表明，骨髓细胞中STAT 3的过度活化同时发挥抗炎和抗肿瘤作用。因此，靶向抑制巨噬细胞中的SOCS 3活性可能是抑制肿瘤转移的治疗性方法。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Inflammation has been demonstrated to play important roles in tumorigenesis, tumor progression, and metastasis. STAT3 has been shown to be frequently activated in a variety of human cancer cells and STAT3 signaling promotes the growth and survival of tumor cells. However, the role of STAT3 of myeloid cells associated with tumors is currently unknown. Suppressor of cytokine signaling-3 (SOCS3) has been shown to be a negative regulator of STAT3. In this study, we used macrophage specific SOCS3 conditional knockout (cKO) mice to investigate the effect of the hyperactivation of STAT3 in macrophages on tumor development and metastasis. In a subcutaneous transplantation model of B16F10 melanoma cells, although tumor sizes were not significantly different, SOCS3-cKO mice survived longer than wild-type (WT) mice did. SOCS3-cKO mice exhibited fewer lung and liver metastatic tumor nodules than WT mice when B16F10 was challenged intravenously. SOCS3(-/-) macrophages stimulated with tumor lysates in vitro exhibited prolonged STAT3 phosphorylation and produced less amount of TNF alpha and IL-6, and higher amount of MCP2/CCL8 than WT macrophages. MCP/CCL8 was induced via STAT3 and exhibited anti-tumor metastatic effect in WT mice. These data suggest that hyperactivation of STAT3 in myeloid cells simultaneously exerted an anti-inflammatory as well as anti-tumor effects. Thus, the targeted inhibition of SOCS3 activity in macrophages may be therapeutic for the suppression of tumor metastasis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.